In this Program Project we plan to expand the evidence indicating that life span is strongly inherited in families with exceptional longevity. As part of the overall enterprise of understanding the heritability of longevity and the contributions of specific genes and their associated phenotypes to it, this project will explore how the incidence of cardiovascular disease is affected by (1) having a parent who survived to the age of 95 years, (2) being a carrier of several alleles identified previously as being candidate promoters of longevity (CETP W, APOC3 CC, and ADIPOQ del/del), (3) having a phenotype characterized by large HDL and LDL cholesterol particle sizes, and (4) having a high level of adiponectin, low levels of CETP and APOC-3. The project will follow two cohorts of 500 people each , all initially free of cardiovascular disease, frequency matched for age and sex. One cohort will consist of the offspring of a parent with exceptional longevity, 95 years or more (OPEL); the other will be the offspring of a parent with usual survival, both parents deceased by age 95 (OPUS). Participants will be followed for three to four years, depending on when they are recruited. The OPEL subjects will have a higher than usual prevalence of longevity associated genes in general, and of the genes targeted by this study in particular. They will also have a higher prevalence of the large lipid particle size phenotype. This enrichment of the study population with these unusual features makes it possible to study the impact of these features on cardiovascular disease incidence. We expect to show a marked reduction in the incidence of cardiovascular disease in OPEL compared to OPUS, in the carriers of the CETP W, APOC3 CC and AIPOQ del/del genotypes, in those with large HDL and LDL cholesterol particle sizes, and in those with high levels of adiponectin, low levels of CETP and APOC-3.